NTP technical report on the toxicity studies of Diethanolamine (CAS No. 111-42-2) Administered Topically and in Drinking Water to F344/N Rats and B6C3F1 Mice.

Abstract

Diethanolamine is a high-production chemical used in cosmetics, in cutting fluids, as a dispersing agent for agricultural chemicals, and as an absorbent for acidic gases. Toxicology studies of diethanolamine were conducted in F344/N rats and B6C3F1 mice of both sexes for 2 weeks (5/sex/species/dose) and 13 weeks (10/sex/species/dose) to characterize and compare the effects of oral and dermal exposure. In addition to histopathology, evaluations included clinical pathology, urinalyses, and sperm morphology or vaginal cytology. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and mouse lymphoma L5178Y cells, analysis of chromosomal aberrations and sister chromatid exchange in Chinese hamster ovary cells, and determination of micronuclei formed in mice during the 13-week dermal exposure study. Groups of rats and mice received drinking water containing diethanolamine at concentrations of up to 10000 ppm during studies of 2 or 13 weeks duration. In the 2-week studies, rats and mice of both sexes received in the were 0, 630, 1250, 5000, and 10000 ppm diethanolamine in the drinking water. In the 13-week studies, rats received 0, 320, 630, 1250, 2500, and 5000 ppm (males) or 0, 160, 320, 630, 1250, and 2500 ppm (females) in drinking water; male and female mice received 0, 630, 1250, 2500, 5000, and 10000 ppm. All female rats in the 2 highest dose groups and 2 males in the 10000 ppm group in the 2-week study died before the end of the study. In the 13-week study, deaths of mice occurred in the 3 highest dose groups; 2 male rats in the top dose group also died. Surviving animals in the higher concentration groups in both studies exhibited depressed weight gains. Rats receiving diethanolamine developed a poorly regenerative, microcytic anemia in both studies. In the 2-week study, dosed male and female rats had increased kidney weights, renal tubular cell necrosis, and decreased renal function; rats in the 13-week study also showed increased incidences or severity of nephropathy, tubular necrosis, and mineralization. Degeneration of the seminiferous tubules of the testis was noted in dosed males in both the 2- and 13-week studies, and sperm motility and count were decreased in the 13-week study. Demyelination in the brain (medulla oblongata) and spinal cord was observed in male and female rats in the 13-week study. In mice, dose-dependent increases in liver weight were observed in males and females in the 2-week study; cytologic alteration and necrosis of individual hepatocytes were observed in the highest dose group. In the 13-week drinking water study in mice, nephropathy and tubular necrosis were observed in males, and degeneration of cardiac myocytes, and hepatocellular necrosis were seen in males and females. Cytologic alteration in the submandibular salivary gland was noted in male and female mice. Hepatocyte cytologic alteration also was noted in all dosed groups of mice. In the 2-week dermal studies, groups of rats and mice were administered daily doses of diethanolamine in 95% ethanol, ranging from 160 to 2500 mg/kg for mice, and from 125 to 2000 mg/kg for rats, 5 days per week. In 13-week studies, dermal doses ranged from 32 to 500 mg/kg for rats, and from 80 to 1250 mg/kg for mice. In the 2-week study, early deaths of male rats and male and female mice occurred in the highest dose groups and in female rats in the 2 highest dose groups (1000 and 2000 mg/kg). Body weight gains were reduced in rats and mice in the higher dose groups. Early deaths in the 13-week study were observed in the highest dose groups of rats (500 mg/kg) and mice (1250 mg/kg). Body weight gains were reduced in rats and mice given the higher doses. Rats in the dermal studies exhibited dose-dependent hematologic and renal function changes similar to those observed in rats in the drinking water study. In addition, in the 2-week study, rats exhibited ulcerative skin lesions at the site of application, accompanied by inflammatory cell infiltration, hyperkeratosis, and acanthosis (hyperplasia) of the epidermis.dermis. Hyperkeratosis, without ulceration, was observed in some animals. Ulceration at the site of application was observed in male and female mice. Acanthosis, without ulceration or inflammatory cell infiltration, was observed in mice in all lower dose groups. In the 13-week study, skin lesions at the site of application included ulceration and inflammation, hyperkeratosis, and acanthosis. Liver weights were increased in male and female rats, but there were no associated histopathological changes. Other treatment-related effects observed in rats included demyelination in the brain and spinal cord, and nephropathy, renal tubular necrosis, and/or tubular mineralization; mice exhibited cytological alterations in the liver and/or hepatocellular necrosis, renal tubular epithelial necrosis, and cardiac myocyte degeneration. In in vitro genetic toxicity studies, diethanolamine was not mutagenic in Salmonella typhimurium or mouse L5178Y TK± cells. Diethanolamine did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, nor did it induce micronuclei in peripheral blood erythrocytes in mice exposed by topical application for 13 weeks. All in vitro studies were conducted with and without S9 activation. Target organs of diethanolamine toxicity identified in these studies included bone marrow, kidney, brain, spinal cord, testis, and skin in rats, and liver, kidney, heart, salivary gland, and skin in mice. A no-observed-adverse-effect-level (NOAEL) was not achieved for hematological changes or nephropathy in rats (<160 ppm), or for cytologic alteration of the liver in mice (<630 ppm) in the drinking water studies. In the dermal studies, a NOAEL was not achieved for hematological changes, nephropathy, or hyperkeratosis of the skin in rats (<32 mg/kg), or for cytologic alteration of the liver or acanthosis of the skin in mice (<80 mg/kg). Synonyms: 2,2&vprime;-iminodiethanol; 2,2&vprime;-iminobisethanol; diethylolamine; bis(hydroxy-ethyl)amine; 2,2'dihydroxydiethylamine; 2,2&vprime;-aminodiethanol.